IAI Accepts, published online ahead of print on 9 April 2007

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Infect. Immun. doi:10.1128/IAI.00147-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Host-dependent trigger of caspases and apoptosis by Legionella pneumophila

Marina Santic, Rexford Asare, Miljenko Doric, and Yousef Abu Kwaik^*

Department of Microbiology and Parasitology, University of Rijeka, Rijeka, Croatia; Department of Microbiology and Immunology, Room 406, University of Louisville College of Medicine, 319 Abraham Flexner Way 55A, Louisville, KY 40202, USA

^* To whom correspondence should be addressed. Email: abukwaik{at}louisville.edu.

The Dot/Icm system of Legionella pneumophila triggers activation of caspase-3 during early stages of infection of human macrophages, but apoptosis is delayed until late stages of infection. During early stages of infection of mouse macrophages the organism triggers rapid caspase-1-mediated cytotoxicity, which is mediated by bacterial flagellin. However, it is not known whether caspase-1 is triggered by L. pneumophila in human macrophages, or whether caspase-3 is activated in permissive or non-permissive mouse macrophages. Using single cell analyses we show that the wild type strain of L. pneumophila does not trigger caspase-1 activation throughout the intracellular infection of human monocytes-derived macrophages (hMDMs), even when the flagellated bacteria escape into the cytoplasm during late stages. Using single cell analyses we show that the Dot/Icm system of L. pneumophila triggers caspase-3 but not caspase-1 within permissive A/J mouse bone marrow-derived primary macrophages by 2-8h, but apoptosis is delayed till late stages of infection. While L. pneumophila triggers a Dot/Icm-dependent activation of caspase-1 in non-permissive BALB/c mouse-derived macrophages, caspase-3 is not activated at any stage of the infection. We show that robust intrapulmonary replication of the wild type strain of L. pneumophila in susceptible A/J mice is associated with late stage Dot/Icm-dependent pulmonary apoptosis and alveolar inflammation. In the lungs of non-permissive BALB/c mice, L. pneumophila does not replicate and does not trigger pulmonary apoptosis or alveolar inflammation. Thus, similar to hMDMs, L. pneumophila does not trigger caspase-1 but triggers caspase-3 activation during early and exponential replication in permissive A/J mouse-derived macrophages, and apoptosis is delayed until late stages of infection. The Dot/Icm type IV secretion system is essential for pulmonary apoptosis in the genetically susceptible A/J mice.